Thrombosis occurring at atherosclerotic plaques is a major cause of morbidity and mortality in the United States. The initial event in thrombus formation is the adhesion of platelets to an injured or diseased arterial wall. Adhesion is enhanced and stabilized by a plasma protein, the von Willebrand Factor, which forms a bridge between components of the vessel wall and receptors on the platelet surface, primarily the glycoprotein Ib/IX/V complex. There are two unique features of this interaction that set it apart from adhesive events involving other cells and plasma proteins. First, the interaction of vWF with platelets is the only reaction that permits platelets to remain attached to vessel walls under the high shear/high flow conditions present in arteries, arterioles, and capillaries. Second, vWF is the only plasma adhesive protein which must undergo a conformation change before it is able to bind to its platelet receptor.
Attempts have been made to prevent thrombus formation by introducing either antibodies (see, e.g., EP 747,060; WO 96/17078; and U.S. Pat. No. 5,336,618) or peptides (see, e.g., U.S. Pat. No. 5,688,912; U.S. Pat. No. 5,493,007; U.S. Pat No. 5,114,842; WO 93/16712; and EP 319,315) that bind to platelet receptors. One problem with the use of such agents is that they are nonselective--interfering with the function of all circulating platelets. The development of an agent that acts specifically at sites of thrombosis to inhibit platelet adhesion would represent a clear advance in the treatment and prevention of stroke, myocardial infarction, and related conditions. Equally important, such an agent might be used diagnostically to identify sites where blood vessels are at risk of becoming occluded.